Study implicates TET1 enzyme as a master regulator in cancer

A new study carried out at the University of Iowa (IA, USA) has shed light on how KRAS silences tumor suppressor genes and has identified a key enzyme in this mechanism. The findings, published recently in Cell Reports, point to the enzyme TET1 as an important target for cancer diagnostics and treatment.

KRAS gene mutations or mutations in the KRAS pathway are observed in approximately one-third of solid tumors. In KRAS-driven cancers, tumor suppressor genes, which usually limit uncontrolled cell growth and promote self-destruction of damaged cells, are silenced through DNA methylation. This new evidence from the University of Iowa indicates that KRAS promotes this DNA methylation-associated gene silencing by inhibiting the TET1 enzyme, which is able to remove methyl marks from DNA.

“This methyl eraser (TET1) is normally expressed in nonmalignant cells, but when KRAS is activated, the eraser is silenced, leading to accumulation of silencing methyl marks,” explained Charles Brenner (University of Iowa), the senior author of the study.

Brenner and lead study author Bo-Kuan Wu (University of Iowa) found that the addition of TET1 back into cells that have become cancerous due to a KRAS mutation resulted in reactivation of tumor suppressor genes, to the extent that uncontrolled proliferation was reduced. The team also discovered that removing KRAS signaling from the cancer cells reduced the cells’ malignancy; however the removal of TET1 was enough to revert them to a cancerous state, even when KRAS signaling was removed.

The findings, which highlight TET1 as a key player in the KRAS pathway and pinpoint where the TET1 enzyme is silenced within the KRAS biochemical cascade, may aid in decisions over which treatments are most likely to effectively treat a patient’s tumor.

Inhibitor drugs that are able to block this pathway are available and could therefore be utilized in patient treatments. “We know that these inhibitors work in some tumors and not in others,” explained Brenner. “We think that the ability of an inhibitor to allow TET1 to be re-expressed may be a very strong biomarker for whether that drug will work in that tumor.”

The team also believe that the ability to reactivate TET1 gene expression in tumor cells could be another method for testing the therapeutic potential of new compounds in the development of cancer treatments.

“We think that activating TET1 may be a general therapeutic strategy for many malignancies,” Brenner concluded.